This invention relates to the cleavage of nucleic acids, especially deoxyribonucleic acid (DNA) and, more specifically, to the cleavage of DNA by propargylic and allenic sulfones.
DNA is a very long, thread-like molecule which exists in the cells of most living organisms and which is intimately involved in the storage and transfer of genetic information. DNA is composed of discrete chemical units in sequences unique to the particular organism from which it is derived.
DNA cleavage is currently a topic of considerable research investigation, due in part to the recognition that certain molecules interact and bind with sites on a DNA molecule on the basis of the site's specific chemical sequence. Some of these DNA cleaving materials can cleave DNA at sequence specific sites. The sequence-specific cleavage of DNA is essential for many techniques in molecular biology, including gene isolation, DNA sequence determination, and recombinant DNA manipulation. Presently, such cleavage is performed largely with naturally-occurring restriction enzymes which bind and cleave DNA at particularly sequenced sites. However, because both the number and sequence specificities of such enzymes are limited, it is presently possible to cleave DNA only at a limited number of recognition sites.
It would be of great advantage to be able to cleave DNA at other predetermined sites; the design of sequence-specific DNA cleaving molecules that go beyond the specificities of natural enzymes could provide this capability. The ability to design molecules with predetermined specificities for selective cleavage would be of great importance for drug design, diagnostics, molecular biology, and materials chemistry.
The capability of selectively targeting a particularly sequenced site on a DNA and modifying it in some manner may thus provide a means of treatment for a disease or condition controlled by that site. For example, it has long been the desire of medicine to disrupt neoplasms such as cancer cells in animals, especially man. Such cells can likely be killed if their DNA were effectively, yet specifically, cleaved. While a number of molecules are known to facilitate DNA strand cleavage, many such compounds are believed to attack DNA in an organism's cells in a non-selective fashion. Because of the toxic nature of such nonselective DNA-reactive compounds, medicinal therapies which employ them have generally been reserved for advanced forms of cancer and other life-threatening diseases. With the advent of molecules which can selectively bind and cleave cancer cell DNA on the basis of a particular chemical sequence, new methods for the design of safe, effective, and highly specific, therapeutic agents, including anticancer agents could likely be developed. Interfering with DNA coding for other biological properties may provide therapeutic routes to non-neoplastic diseases as well. Accordingly, much effort has been directed toward the development of molecules that target and cleave chemically specific sites along a strand of DNA.
Both naturally-occurring and synthetic compounds have demonstrated the ability to cleave DNA under certain conditions; however, the presence of other reactive species has in many cases been a necessary predicate to effect the desired cleavage. For example, Zein, et al., Science, 240, 1198 (1988), have recently reported that a member of the calichemicin class of antibiotics cleaves DNA in a site-specific manner and that the ability to induce double-stranded DNA cleavage may account for the demonstrated antitumor activity of structurally related compounds. However, the mode of action for compounds belonging to these classes is thought to depend upon the attack of nucleophilic species. After recognition and interaction of a properly structured molecule from this class with DNA, the nucleophile is thought to trigger a sequence of intramolecular reactions centering on the unique bicyclic core structure. These reactions are believed to generate a highly reactive benzenoid diradical species through the cyclization of the conjugated enediyne moiety present within the bicyclic core. This species, in turn, is thought to react with and damage DNA's phosphate backbone.
While calichemicin and related compounds appear capable of cleaving DNA in nucleophilic environments, it would be of great advantage to be able to effect DNA cleavage under a wide variety of conditions, such as might be found within the human body, and with broad specificity.
It is therefore an object of this invention to provide chemical compounds which will cleave DNA.
It is another object of this invention to provide chemical compounds which will cleave DNA in a site-selective fashion.
It is yet another object of this invention to provide chemical compounds which will cleave DNA under a variety of conditions, especially under physiological conditions.